Erythromycin derivatives, method for preparing same and use thereof as drugs

ABSTRACT

The compounds of formula (I): ##STR1## in which R is a hydrogen atom, an alkyl, optionally substituted by a halogen atom or a (CH 2 ) m  Ar radical or a ##STR2## in which m represents an integer (1-8), n and p, identical or different, represent an integer (0-6), A and B, identical or different, represent a hydrogen or a halogen or an alkyl and Ar represents an aryl or heteroaryl, and Z represents a hydrogen or the remainder of a carboxylic acid, preparation process and use as medicaments.

This application is a 371 of PCT/FR97/01372 filed Jul. 23, 1997.

The present invention relates to new derivatives of erythromycin, theirpreparation process and their use as antibiotics.

A subject of the invention is the compounds of formula (I): ##STR3## inwhich R represents a hydrogen atom, an alkyl containing up to 12 carbonatoms, optionally substituted by a halogen atom or a (CH₂)_(m) Arradical or a ##STR4## radical, in which m represents an integercomprised between 1 and 8, n and p, identical or different, represent aninteger comprised between 0 and 6, A and B, identical or different,represent a hydrogen or a halogen atom or an alkyl radical containing upto 8 carbon atoms and Ar represents an aryl or heteroaryl radical,optionally substituted, and Z represents a hydrogen atom or theremainder of a carboxylic acid containing up to 18 carbon atoms.

In the definition of the substituents, the alkyl radical can be amethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or terbutyl,cyclobutyl, cyclopentyl, cyclohexyl, decyl or dodecyl radical. Thehalogen is preferably a fluorine, chlorine or bromine atom. The arylradical can be a phenyl or naphthyl radical. The heteroaryl radical canbe a thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl,thiadiazolyl, pyrazolyl or isopyrazolyl radical, a pyridyl, pyrimidyl,pyridazinyl or pyrazinyl radical, or also an indolyl, benzofuranyl,benzothiazyl or quinolinyl radical. The aryl or heteroaryl radical canbe substituted by one or more substituents chosen from the groupconstituted by hydroxyl radicals, halogen atoms, NO₂ radicals, C.tbd.Nradicals, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl,S-alkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl or N-alkynylradicals, containing up to 12 carbon atoms optionally substituted by oneor more halogen atoms, the ##STR5## radical, R_(a) and R_(b), identicalor different, representing a hydrogen atom or an alkyl radicalcontaining up to 12 carbon atoms, the ##STR6## radical, R₃ representingan alkyl radical containing up to 12 carbon atoms, or an optionallysubstituted aryl or heteroaryl radical, carboxylic aryl, O-aryl orS-aryl radicals or heterocyclic aryl, O-aryl or S-aryl radicals with 5or 6 members containing one or more heteroatoms, optionally substitutedby one or more of the substituents mentioned below.

As the preferred heterocycle radical, the following radicals can bementioned: ##STR7## and the heterocyclic radicals envisaged in theEuropean Patent Applications 487411, 596802, 676409 and 680967.

The radicals can be substituted by one or more of the substituentsindicated above.

A more particular subject of the invention is the compounds of formula(I) in which Z represents a hydrogen atom, the compounds of formula (I)in which R represents a hydrogen atom, the compounds of formula (I) inwhich R represents (CH₂)_(m) Ar, m and Ar retaining the same meaning aspreviously, and in particular those in which R represents a (CH₂)_(m),Arradical, in which m' represents the number 3, 4, 5 or 6, such as, forexample, those in which Ar represents a 4-quinolinyl radical optionallysubstituted on one and/or the other of the 2 quinoline rings and quiteespecially those in which Ar represents a non-substituted 4-quinolinylradical, or also the compounds of formula (I) in which Ar represents aradical: ##STR8## optionally substituted on one and/or the other of the2 rings and quite especially those in which the Ar radical is notsubstituted.

A quite particular subject of the invention is the compounds whosepreparation is given hereafter in the experimental part and inparticular the compound of Example 4.

The products of general formula (I) have a very good antibiotic activityon gram .sup.⊕ bacteria such as staphylococci, streptococci,pneumococci.

The compounds of the invention can therefore be used as medicaments inthe treatment of infections caused by susceptible germs and inparticular, in that of staphylococcia, such as staphylococcalsepticemias, malignant staphylococcia of the face or skin,pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons,erysipelas and acne, staphylococcia such as acute primary orpost-influenzal angina, bronchopneumonia, pulmonary suppuration,streptococcia such as acute angina, otitis, sinusitis, scarlet fever,pneumococcia such as pneumonia, bronchitis; brucellosis, diphteri,gonococcal infection.

The products of the present invention are also active against infectionscaused by germs such as Haemophilus influenzae, Rickettsies, Mycoplasmapneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma or by germs ofthe Mycobacterium genus.

Therefore, a subject of the present invention is also, as medicamentsand, in particular antibiotic medicaments, the products of formula (I)as defined above, as well as their addition salts with pharmaceuticallyacceptable mineral or organic acids.

A more particular subject of the invention is, as medicaments and, inparticular antibiotic medicaments, the products of the examples.

A subject of the invention is also the pharmaceutical compositionscontaining at least one of the medicaments defined above as activeingredient.

These compositions can be administered by buccal, rectal, parenteralroute or by local route as a topical application on the skin and mucousmembranes, but the preferred administration route is the buccal route.

They can be solid or liquid and be presented in the pharmaceutical formscommonly used in human medicine, such as for example, plain orsugar-coated tablets, capsules, granules, suppositories, injectablepreparations, ointments, creams, gels; they are prepared according tothe usual methods. The active ingredient or ingredients can beincorporated with excipients usually employed in these pharmaceuticalcompositions, such as talc, gum arabic, lactose, starch, magnesiumstearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,various wetting, dispersing or emulsifying agents, preservatives.

These compositions can also be presented in the form of a powderintended to be dissolved extemporaneously in an appropriate vehicle, forexample apyrogenic sterile water.

The dose administered is variable according to the illness treated, thepatient in question, the administration route and the productconsidered. It can be, for example, comprised between 50 mg and 500 mgper day by oral route, for an adult for the product of Example 4.

The compounds of formula (II) used as starting products are describedand claimed in the European Patent Application 0596802.

A subject of the invention is also a process characterized in that acompound of formula (II): ##STR9## in which Z retains its previousmeaning, is subjected to the action of hydroxylamine or a hydroxylaminehydrohalide, in order to obtain the compound of formula (I_(A)):##STR10## which, if desired, is subjected to the action of amethanolysis agent in position 2', in order to obtain the correspondingcompound of formula (I_(B)) in which Z represents a hydrogen atom##STR11## then the compound (I_(A)) or (I_(B)) is subjected to theaction of a compound of formula (III):

    R'Hal                                                      (III)

in which R' has the same meaning as R with the exception of the hydrogenand Hal represents a halogen atom, in order to obtain the correspondingcompound of formula (I_(C)), which is optionally subjected to the actionof a hydrogenation agent of the optional double bond of the ##STR12##radical and/or to the action of an agent which releases the hydroxylfunction in position 2'.

A subject of the invention is also the compounds of formula (III) whosepreparation is given hereafter in the experimental part.

In a preferred implementation of the process of the invention:

the operation is carried out in the presence of an excess ofhydroxylamine or hydroxylamine hydrohalide, in a solvent such asacetonitrile, dioxane, dimethylformamide, tetrahydrofuran,dimethoxyethane or dimethylsulphoxide,

the release of the hydroxyl in position 2' is carried out bymethanolysis,

the esterification in position 2' is carried out according to standardprocesses, Hal in the compound of formula (III) is preferably a bromine,chlorine or iodine atom,

the reaction between compound (I_(A)) and compound (III) takes place inthe presence of sodium hydride,

the optional reduction of the chain ##STR13## is carried out usinghydrogen in the presence of a catalyst such as palladium, platinum andequally well in the presence or not of an acid such as hydrochloric acidor acetic acid.

The following examples illustrate the invention:

EXAMPLE 1

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl (hydroxyimino))-erythromycin

200 cm³ of acetonitrile and 20 g of11-deoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl)oxy))-12-O-(11H-imidazol-1-yl) carbonyl)-6-O-methyl-3-oxo-erythromycin2'-acetate is added to a solution containing 5.9 g of hydroxylaminehydrochloride and 20 cm³ of water. Agitation is carried out for 3 hours,followed by evaporating to dryness, taking up in methanol and agitatingagain for 20 hours at ambient temperature. After evaporating to dryness,the residue is taken up in methylene chloride, washed with water,extracted with ethyl acetate, dried and evaporated to dryness. 17.4 g ofproduct is obtained which is chromatographed on silica eluting with anAcOEt-TEA-MeOH mixture (98-0.75-0.75). 2.06 g of product is obtained bychromatography eluting with an isopropyl ether-TEA-MEOH system (90-5-5).The sought product is obtained.

NMR spectrum (400 Mhz in CDCl₃) ppm 0.88: CH₃ CH₂ ; 1.2: 8 Me; 1.25: 5'Me; 1.31: 4 Me; 1.39: 2 Me; 1.33-1.49: 6 and 12 Me; 1.55 and 1.94: CH₂in position 13; 1.67 and 1.89: CH₂ in position 7; 1.67: CH₂ in position3'; 2.27: N(Me)₂ ; 2.46: H3'; 2.68: 6 OMe; 2.72: H8; 3.04: H4; 3.14:H10; 3.18: H2'; 3.57: H5'; 3.82: H11; 3.84: H2; 4.26: H5; 4.35: H1';5.14: H13.

EXAMPLE 2

(E)11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl (((3-phenyl 2-propenyl)oxy)imino))-erythromycin

A solution containing 328 mg of the product of Example 1 and 4 cm³ ofDMF is cooled down to 0° C. 41 mg of sodium hydride at 60% in oil isadded. Agitation is carried out for 15 minutes at 0° C. and 113 mg ofcinnamyl bromide in solution in 2 ml of DMF on siliporite is added. Thereaction medium is poured over ice, extracted with methylene chloride,washed with water, dried and evaporated to dryness. 420 mg of product isobtained which is purified on silica eluting with an isopropylether-triethylamine-methanol mixture (9-0.4-0.4). The sought product isobtained.

NMR spectrum (300 Mhz in CDCl₃) ppm 0.74: CH₃ CH₂ ; 1.14: 8 and 10 Me;1.24: 5' Me; 1.31: 4 Me; 1.41 and 1.49: 6 and 12 Me; 1.39: 2 Me; 1.50and 1.82: CH₂ in position 14; 1.25 and 1.68: CH₂ in position 4'; 2.29:N(Me)₂ ; 2.48: H3'; 2.80: H8; 2.83: 6 Ome; 3.03: H10; 3.19: H2'; 3.54:H5'; 3.84: H2; 4.18: H11; 4.24: H5; 4.29: H1'; 4.52 and 4.61: OCH₂ CH₃ ;5.11: H13; 6.40 and 6.76: E ethylenics; 7.2 to 7.43: aromatics.

EXAMPLE 3

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl((3-phenylpropoxy)imino))-erythromycin

A mixture containing 57 mg of the product of Example 2, 15 ml of ethylacetate and 8 mg of palladium on carbon is placed under a hydrogenatmosphere and agitation is carried out for 2 hours, followed byfiltering, rinsing with ethyl acetate and evaporating to dryness. 56 mgof crude sought product is obtained which is purified on silica elutingwith an isopropyl ether-triethylamine-methanol mixture (9-0.45-0.45). Inthis way 45 mg of sought product is obtained.

NMR spectrum (CDCl₃) ppm 0.89: CH₃ CH₂ ; 1.13-1.15-1.24-1.29-1.36: CH₃--CH; 1.37-1.50: 6 and 12 Me; 1.99: Central CH₂ ; 2.27: N(Me)₂ ; 2.46:H3'; 2.69: 6 OMe; 2.74: CH₂ Ph and H8; 2.97: H10; 3.08: H4; 3.17: H2';3.52: H5'; 3.82: H2; 3.90 and 3.98: CH₂ O--N; 4.2: H5; 4.21: H11; 4.26:H1'; 5.12: H13; 7.1 to 7.3: Phenyl.

EXAMPLE 4

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl (3-(4-quinolinyl) propoxy)imino)-erythromycin

The operation is carried out as in Example 2, starting with the productof Example 1 and the product of Preparation 1, the sought product isobtained. M.p.=224° C.

NMR spectrum (CDCl₃) ppm 0.88: CH₃ CH₂ ; 1.13: 8 Me; 1.18: 10 Me; 1.23:5' Me; 1.29: 4 Me; 1.35: 2 Me; 1.34-1.51: 6 and 12 Me; 1.25 and 1.69:CH₂ in position 4'; 1.59 and 1.92: CH₂ in position 7; 2.13: Central CH₂of the chain; 2.28: N(Me)₂ ; 2.45: H3'; 2.68: 6 OMe; 2.72: H8; 3.05:H10; 3.07: H4; 3.17: H2'; 3.28: CH₂ C═; 3.52: H5'; 3.89: H2; 4.01 and4.08: CH₂ ONC═O; 4.16: H11; 4.2: H5; 4.27: H1'; 5.12: H13;7.33-7.56-7.69-8.10-8.80: quinoline.

EXAMPLE 5

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl(3-(4-(3-pyridinyl)-1H-imidazol-1-yl) propoxy) imino)-erythromycin

The operation is carried out as in Example 2, starting with the productof Example 1 and the product of Preparation 2, the sought product isobtained.

NMR spectrum (CDCl₃) ppm 0.88: CH₃ CH₂ ; 1.15: 10 Me; 1.17: 8 Me; 1.24:5'Me; 1.29: 4 Me; 1.35: 2 Me; 1.37-1.51: 6 and 12 Me; 1.30-1.75: CH₂ inposition 4'; 1.62-1.72: CH₂ in position 4'; 1.62-1.72: CH₂ in position7; 1.60-1.92: CH₂ in position 14; 2.17: Central CH₂ ; 2.29: NMe₂ ; 2.48:H3'; 2.68: 6 O Me and H8; 3.06: H3; 3.08: H10; 3.19: H2'; 3.53: H5';2.83: H2; 3.98: CH₂ --N; 4.05: H11; 4.21: H5; 4.27: H1'; 4.15 to 4.40:NO--CH₂ ; 5.09: H13; 7.49 and 7.68: imidazole; 7.29-8.1-8.46-8.90:pyridine.

Preparation 1: 4-(3-iodopropyl) quinoline

Stage A: ethyl4-(3-chloropropyl)-2-(diethoxyphosphinyl)-1(2H)-quinolinecarboxylate

A solution of 7.0 g of ethyl 2-(diethoxyphosphinyl)1(2H)-quinolinecarboxylate and 70 ml of THF is cooled down to -65° C.17.6 ml of butyllithium and 4 ml of bromochloro-propane are added over15 minutes. Agitation is carried out for 3 hours 30 minutes, thereaction medium is poured into 50 cm³ of ice-cooled water, followed byextraction with ethyl acetate, washing with water, drying andevaporating to dryness. The crude sought product is obtained which ispurified by chromatography on silica eluting with a cyclohexane-ethylacetate mixture (4-6), in this way 6.541 g of the sought product isobtained.

NMR spectrum (250 Mhz in CDCl₃) ppm 0.98-1.19-1.33: CH₃ ; 2.01: CentralCH₂ ; 2.55 to 2.85: ═CH₂ ; 3.59: CH₂ --CH₂ --X; 3.71 to 4.14: CH₂ ofPOEt; 4.30: CH₂ of CO₂ Et; 4.30: CH₂ of CO₂ Et; 5.57: P--CH; 5.92:═CH--CH--P; 7.11-7.26-7.60: Aromatics.

Stage B: 4-(3-chloropropyl) quinoline

6.5 g of the product of Stage A, 65 cm³ of ethyl alcohol and 65 cm³ of2N soda are agitated at 120° C. for 2 hours. After evaporating,extraction is carried out with ether, followed by washing with water,drying and evaporating to dryness. 1.87 g of product is obtained whichis chromatographed on silica eluting with a methylene chloride-ethylacetate mixture (8-2). 0.617 g of sought product is obtained.

NMR spectrum (CDC1₃) ppm 2.24: Central CH₃ ; 3.27: CH₂ C═; 3.62: CH₂--X; 7.28-7.59-7.72-8.06-8.13-8.83: quinoline.

Stage C: 4-(3-iodopropyl) quinoline

A mixture of 268 mg of the product of Stage B, 5 ml of acetone, 1.042 gof sodium iodide and 30 mg of tetrabutylammonium iodide is agitated for4 hours at 60° C. The acetone is evaporated off, the residue is taken upin methylene chloride, followed by washing with a 10% solution of sodiumsulphite, drying and evaporating to dryness. 3.91 mg of sought productis obtained.

Preparation 2: 3-[1-(3-bromopropyl)-1H-imidazol-4-yl]-pyridine.

A solution containing 400 mg of 3-(1H-imidazol-4-yl) pyridine, 3 ml ofDMF and 132 mg of sodium hydride at 60% in oil is agitated for 1 hour at60° C. A solution of 3.22 g de dibromopropane in 2 ml of DMF is addeddropwise. Agitation is carried out for 1 hour at ambient temperature,followed by pouring into ice-cooled water, extracting with ethylacetate, drying and evaporating to dryness. The product obtained ischromatographed on silica eluting with a methylene chloride-methanolmixture (9-1). 306 mg of sought product is obtained.

Example of Pharmaceutical Composition

Compounds were prepared containing:

Product of Example 4 . . . 150 mg

Excipient s.q.f. . . . 1 g

Detail of excipient: starch, talc, magnesium stearate

Pharmacological Study of the Products of the Invention

Method of dilutions in liquid medium

A series of tubes are prepared in which the same quantity of sterilenutritive medium is distributed. Increasing quantities of the product tobe studied are distributed into each tube, then each tube is sown with abacterial strain.

After incubation for twenty-four hours in a heating chamber at 37° C.,the growth inhibition is evaluated by transillumination, which allowsthe minimal inhibitory concentrations (M.I.C.) to be determined,expressed in micrograms/cm³.

The following results were obtained with the product of Example 4(reading after 24 hours):

    ______________________________________                                        GRAM.sup.+  bacterial strains                                                 ______________________________________                                        Staphylococcus aureus 011UC4                                                                        0.04                                                    Staphylococcus aureus 011G025I                                                                      0.15                                                    Staphylococcus epidermidis 012GO11I                                                                 0.15                                                    Streptococcus pyogenes                                                                              ≦0.02                                            group A 02A1UC1                                                               Streptococcus agalactiae                                                                            ≦0.02                                            group B 02B1HT1                                                               Streptococcus faecalis                                                                              ≦0.02                                            group D 02D2UC1                                                               Streptococcus faecium ≦0.02                                            group D 02D3HT1                                                               Streptococcus sp      ≦0.02                                            group G 02G0GR5                                                               Streptococcus mitis 02mitCB1                                                                        0.04                                                    Streptococcus agalactiae                                                                            0.08                                                    group B 02B1SJ1                                                               Streptococcus pneumoniae 032UC1                                                                     ≦0.02                                            Streptococcus pneumoniae 030SJ5                                                                     0.04                                                    ______________________________________                                    

In addition, the product of Example 4 has demonstrated a useful activityon the gram.sup.⊖ bacterial strains: Haemophilus Influenzae 351HT3,351CB12, 351CA1 and 351GR6.

What is claimed is:
 1. A compound of the formula ##STR14## wherein R isselected from the group consisting of hydrogen, alkyl of 1 to 12 carbonatoms optionally substituted by halogen, --(CH₂)_(m) --Ar and ##STR15##m is an integer from 1 to 8, n and p are individually an integer from 0to 6, A and B are individually selected from the group consisting ofhydrogen, halogen and alkyl of 1 to 8 carbon atoms, Ar is optionallysubstituted aryl or heteroaryl and Z is hydrogen or acyl of an organiccarboxylic acid of up to 18 carbon atoms.
 2. A compound of claim 1wherein Z is hydrogen.
 3. A compound of claim 1 wherein R is halogen. 4.A compound of claim 1 wherein R is --(CH₂)_(n) --Ar.
 5. A compound ofclaim 4 wherein R is --(CH₂)_(n) --Ar and m' is an integer from 3 to 6.6. A compound of claim 5 wherein Ar is 4-quinolinyl optionallysubstituted on at least one quinoline ring.
 7. A compound of claim 5wherein Ar is 4-quinolinyl.
 8. A compound of claim 5 wherein Ar is##STR16## optionally substituted on at least one of the rings.
 9. Acompound of claim 8 wherein Ar is unsubstituted.
 10. A compound of claim1 which is 11,12-dideoxy-3-de (2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl(3-(4-quinolinyl) propoxy)imino) erythromycin.
 11. An antibacterial composition comprising anbactericidally effective amount of a compound of claim 1 and an inertpharmaceutical carrier.
 12. A method of treating bacterial infections inwarm-blooded animals comprising administering to warm-blooded animals abactericidally effective amount of a compound of claim
 1. 13. A compoundselected from the group consisting of:-4-(3-iodopropyl)-quinoline and-3-[1-(3-bromopropyl)-1H-imidazo]-4-yl]-pyridine.